Diabetic nephropathy (DN), the most lethal diabetic micro-vascular complication, occurs in approximately 30% of patients with diabetes. It is apparent, therefore, that prevention, definition of at risk populations and effective treatment of DN is of critical importance for the well-being of individuals with diabetes. The clinical hallmarks of DN include progressive albuminuria followed by a gradual decline in renal function concluding, after 5-15 years, with end-stage renal disease. Available therapeutic options have all contributed to a gradual reduction in progression of DN. However, none of these interventions, independently nor concurrently, effectively prevents the development or progression of DN in the majority of these patients. Effective prevention and treatment of DN will be most expeditiously achieved by investigative strategies pinpointing the markers and mechanisms involved in progressive kidney damage in each patient afflicted with this complication. Despite decades of research into the mechanisms of DN, and general agreement about some critical pathways, the mechanisms defining initiation, progression and response to therapies remain a mystery. The overarching hypothesis of this application states that molecular markers are able to stratify diabetic patients into distinct sub-cohorts with variable disease outcome. The main aim of this study is to define molecular markers predictive of the development of progressive DN in patients with Types 1 and 2 diabetes. The following step-wise approach will be employed to identify predictors of renal function loss in DN: Aim 1: Define candidate mRNA predictors of renal function in patients with incipient (stage 3) DN using established genome wide expression profiles obtained from renal biopsies of DN. Test mRNA predictor panel in a second, independent cohort of patients with DN who also have defined long-term renal outcome. Aim 2: Define candidates for non-invasive protein based screening from mRNA marker panel. Test the predictive power of the non-invasive protein marker candidates in blood and urine samples from DN patients with defined long-term renal outcome. The step wise approach combining intra-renal gene expression profiles with highly sensitive and focused proteomic analysis will allow us to filter the most promising candidates for a noninvasive prediction of progressive DN.